Malaria remains a leading cause of morbidity and mortality worldwide, killing approximately 781,000 people in 2009. Drug therapy remains one of the major strategies of malaria control. The spread of drug resistant P. falciparum, however, remains a major threat to the goal of eradication, requiring monitoring of the efficacy of the newly deployed artemisinin based combination treatments (ACTs). Monitoring of recently removed drug pressures also remains important given 1) the possible re-expansion of susceptible P. falciparum (as a result of a fitness cost on resistance parasites) to these drugs after a period if unused and 2) their potential for redeployment in combination therapy or in increased doses. Current monitoring methods include follow up of therapeutic failures in vivo, phenotypic determination of parasite sensitivity by short-term ex vivo drug testing and studies of molecular markers associated with drug resistance are surveyed to monitor drug sensitivity to P. falciparum. The question of how resistance will spread in a country with distinct eco-epidemiological zones has not been investigated. This is important because accounting for the effects of transmission in the various eco- epidemiologist in drug efficacy monitoring can identify hotspots for the spread of resistance that will be used to maximize the efficiency of existing sentinel systems for efficacy monitoring. The goal of this study is to improve current methods for surveying drug sensitivity, and elucidate the importance of clonal multiplicity, a measure of transmission intensity on the surveillance of drug resistance in two major eco-epidemiological zones of Ghana. Specifically, we will measure and compare the clinical and parasitological efficacy of anti-malarial drugs in two distinct ecological zones, determine the multiplicity of infections and its association with drug resistance and characterize and compare the frequency of known drug resistance markers in two eco-epidemiological zones and their correlations with ex vivo drug response. The study will be conducted in Hohoe, in the Forest ecological zone and Ada in the Coastal Savannah zone of Ghana. A one-arm prospective evaluation of clinical and parasitological responses to treatment for uncomplicated malaria with Amodiaquine -Artemisinin (AA) or Artemisinin Lumifantrine (AL) will be conducted. A total of 200 children/year (800 over four years) with uncomplicated malaria in District hospitals of the two study sites who meet the study inclusion criteria will be enrolled during the peak of the malaria transmission season (June-October). These children will be treated on site with AA or AL following standard of care and monitored for 28 days. When we recruit the 100th child, collection will be done for that site. The follow-up will consist of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations. When a child does not return to a scheduled visit, a research staff will be sent to the child's house to minimize losses to follow-up. On the basis of the results of these assessments, the children will be classified as having therapeutic failure (early, late clinical, ad late parasitological) or an adequate response (not presenting neither type of therapeutic failure). PCR analysis will be used to distinguish between a true recrudescence due to treatment failure and episodes of re-infection (msp1 and msp2 typing). Ex vivo drug testing of samples collected before treatment will be use to determine non-clinical phenotypes of drug response by measuring IC50.s. Polymorphisms in single copy P. falciparum vaccine candidate antigens (msp1, msp2 and csp) will be genotyped to assess MOI and putative molecular markers associated with drug resistance will be characterised to determine their frequency and association with drug resistance phenotypes and MOI. In addition, an annual cross-sectional survey of 100 school children per study area (200 samples from the two ecological zones and, 800 samples over a four year period) will be recruited for multiplicity of infection (MOI) assessment of the population. We will test the hypothesis that the prevalence of resistant parasites will decrease with polyclonal infections at high malaria transmission intensity (Forest ecological zone) and increase with clonal infections at low malaria transmission (Coastal Savannah ecological zone).